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Regulation of the Cardiac Na~+/Ca~(2+) Exchanger by Calcineurin and Protein Kinase C

机译:Calcineurin和蛋白激酶C的心脏Na + / Ca〜(2+)交换剂的调节

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Na~+/Ca~(2+) exchanger (NCX) activity is markedly inhibited in hypertrophic neonatal rat cardiomyocytes subjected to chronic phenyle-phrine treatment. This inhibition is reversed partially and independently by acute inhibition of calcineurin and protein kinase C (PKC) activities. Similar NCX inhibition occurs in CCL39 cells expressing cloned wild-type NCX1, when they are infected with adenoviral vectors carrying activated calcineurin A and then treated acutely with phorbol myris-toyl acetate or protein phosphatase-1 inhibitors. The data obtained with these cells suggest that calcineurin activity, PKCα-mediated NCX1 phos-phorylation, and the central loop of NCX1 (possibly its β1 repeat) are required for the observed NCX inhibition. We observe partial inhibition of NCX activity independent of NCX1 phosphorylation when CCL39 cells are infected with activated calcineurin A but not further treated with phorbol myristoyl acetate or phosphatase inhibitors. Calcineurin thus appears to downregulate NCX activity via two independent mechanisms, one involving NCX1 phosphorylation and the other not involving NCX1 phosphorylation. These data indicate the existence of a novel regulatory mechanism for NCX1 involving calcineurin and PKC, which may be important in cardiac pathology.
机译:Na〜+ / Ca〜(2+)交换剂(NCX)活性在经过慢性酚类冻治疗的肥厚新生大鼠心肌细胞中显着抑制。通过钙素蛋白和蛋白激酶C(PKC)活性的急性抑制,该抑制部分和独立地逆转。当克隆野生型NCX1的CCl39细胞中发生类似的NCX抑制,当它们被携带活化的钙素A的腺病毒载体感染,然后用苯甲酸骨苷 - 聚乙酸酯或蛋白质磷酸酶-1抑制剂治疗。通过这些细胞获得的数据表明,观察到的NCX抑制需要钙肌苷活性,PKCα介导的NCX1 PHOS-PHORYLATION,以及NCX1(可能其β1重复)的中心环。我们观察与NCX1磷酸化无关的NCX活性的部分抑制当CCL39细胞用活化的钙素蛋白A感染但不再用磷酸氨基脲或磷酸酶抑制剂进行进一步处理。因此,钙素似乎通过两个独立的机制来下调NCX活性,涉及NCX1磷酸化,另一个不涉及NCX1磷酸化。这些数据表明存在涉及钙皮林和PKC的NCX1新调节机制,这在心脏病理学中可能是重要的。

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